This invention relates to a composition and method of manufacture and use in which xanthan gum is combined with an active pharmaceutical or other ingredient in a compacted dose form for delivering the active ingredient to the gastro-intestinal tract over a sustained period.
Sustained or slow release compositions containing pharmaceutical medications or other active ingredients are designed to contain higher concentrations of the medicament or ingredient and are prepared in such a manner as to effect sustained or slow release into the gastro-intestinal digestive tract of humans or animals over an extended period of time. Well absorbed oral sustained or slow release therapeutic drug dosage forms have inherent advantages over conventional, immediate release dosage forms. The advantages include less frequent dosing of a medicament and resultant patient regime compliance, a more sustained drug blood level response, the possibility of effecting therapeutic action with less ingested drug, and the mitigation of side effects. By providing a slow and steady release of the medicament over time, absorbed drug concentration spikes are mitigated or eliminated by effecting a smoother and more sustained blood level response.
Many therapeutic agents, medicaments, or other active ingredients have a wide window for absorption, meaning that the drug has been demonstrated to be well absorbed along the entire digest tract. Such agents, medicaments, or other active ingredients are then logical candidates for possible dosage as a sustained or slow release medication.
Sustained or slow release therapeutic dose forms are based on many and varied principles. For example, one of the techniques of preparation involves formation of the drug in generally spherical pellet form wherein a specific quantity of pellets are set aside for immediate release and the remaining drug pellets or spheres are coated with various thicknesses of a suitable fat, or resinous, or fatty resinous like coating. When fractions of the pellets are blended together and then filled into capsules or pressed into tablets, without destroying the integrity of the coatings, suitable slow or sustained release dose forms may be effected. Another technique is to admix the therapeutic agent with fats and solid polyhydric alcohols, such as polyoxyethylene glycol, and/or a solid surfactant, such as polyoxyethylene glycol distearate, and press the mixture into tablets to form an erosion matrix to effect slow or sustained release dosage forms. Another method employs the use of a therapeutic agent bound to an ion exchange resin or otherwise complexed with an organic or inorganic molecule and imbedded in a waxy core or granule and administered in capsule or pressed tablet form. Still another method employs the use of an indigestible film former such as methylcellulose applied to a powder or granule base containing a therapeutic agent followed by subsequent forming into compressed tablets to effect slow or sustained release. Yet another method employs a tablet containing a specific drug coated with an indigestible film in which the film is pierced by a laser beam to allow for a small and precise portal from which the drug is slowly released.
As a result of the increased awareness of the importance of hypercholesterolemia and its relationship to coronary heat disease during the last several years, there has been an increased emphasis on treatment with niacin (nicotinic acid). Guidelines for adults have recently been published by the National Cholesterol Education Program, coordinated by the National Heart, Lung and Blood Institute, which state that a desirable blood cholesterol level is below 5.17 mmol/liter. Approximately half of adults screened have been found to have a total blood cholesterol level above the desired range, and accordingly, are encouraged to see a physician for further analysis and instruction. It has been recommended that clinicians use a bile acid sequesterant or niacin as first line therapy for treatment of hypercholesterolemic patients. Niacin is also the oldest of the pharmacologic agents used in the treatment of hyperlipidemia and, since its introduction in 1955, it has been in continuous use either monadically, or in combination with bile acid binding resin therapy.
In doses of 3-6 g/day, which exceed its requirements as a B Vitamin, niacin (but not niacinamide) is highly effective in reducing elevated levels of plasma cholesterol and triglycerides. Niacin inhibits adipose tissue lipolysis, reduces plasma free fatty acid levels and decreases very low density lipoprotein synthesis, thereby decreasing the production of low density lipoproteins from the very low density lipoproteins. Niacin is of demonstrated value in preventing manifestations of arteriosclerotic heart disease, having been shown to decrease recurrent nonfatal myocardial infarction in the coronary drug project by 40% without concurrent increase in mortality from nonarteriosclerotic causes as has been observed with clofibrate.
Niacin is readily absorbed from the stomach and intestinal tract and has no difficulty passing the tissue barrier. Following per os administration of a tablet or capsule dosage of niacin peak plasma levels are obtained within 15-30 minutes in humans. The drug is rapidly distributed in the various tissues including kidney and adipose tissue with a slower metabolism of liver and brown fat. Also of note is the observation that niacin has the ability to penetrate the blood brain barrier.
Niacin is rapidly eliminated from plasma and its elimination halflife in humans is 20-45 minutes. Although large doses of 3-6 g/day of niacin are required to decrease circulating cholesterol and triglycerides in humans, it does not appear that the high peak serum levels attained are required, since the lipid lowering effect is maintained after plasma niacin levels are below the limit of sensitivity of the analytical method used. Thus, there is no correlation between systemic levels of niacin and its pharmacological effect.
The chief drawback to using niacin in the treatment of hyperlipidemia is facial and truncal flushing, which occurs in nearly all users shortly after ingestion of tablets with as small a dosage as 75 mg of niacin per tablet. It appears that niacin induces flushing by increasing the formation and/or release of some prostaglandin, which in turn increases the production of cyclic amp. However, this mechanism does not appear to mediate the effect of niacin on lipolysis. The side effects of truncal flushing, nausea, gastro-intestinal upset, and rectal itching experienced following the ingestion of high potency niacin tablets (500 mg/tablet) has contributed to patient dropout of niacin therapy introduced to treat hyperlipidemia.
It has been difficult to produce a slow or sustained release niacin product by the conventional methods of barrier coating or erosion-type mechanisms. The classic concept of a sustained release dosage regimen is to release 20-35% of the therapeutic agent within the first hour and to sustain the remaining portion of the therapeutic agent over a 8-12 hour period. When one considers that the niacin therapeutic dose is 500-1000 mg and that niacin will cause a flushing response in most subjects with a dosage release of more than 75 mg within a one hour period, the problem becomes apparent. Nicobid, marketed by Armour Pharmaceuticals, has been the most widely marketed sustained release dose form of niacin in recent years. Clinical evaluations of the Nicobid dose form of 500 mg niacin per tablet indicate that the side effects have still not been ameliorated, and the main side effect of flushing is still responsible for a patient dropout rate approaching 20%. Therefore, some new method of slow release is required to cope with the specific problem presented by the niacin dose form requirements.
Bearing in mind the problems and deficiencies of the prior art, it is therefore an object of the present invention to provide a composition and method of manufacture and use which delivers an active pharmaceutical or other ingredients in a dose form to the gastro-intestinal tract of humans and animals over a sustained period.
It is another object of the present invention to provide a composition which delivers niacin, in large dose forms well above 75mg, to the gastro-intestinal tract without the side effects of flushing and itching.
It is a further object of the present invention to provide a sustained release composition and method of manufacture and use which is useful with a wide number of active pharmaceutical and other ingredients.
It is yet another object of the present invention to provide a composition which delivers active pharmaceutical and other ingredients in which the active ingredients may be present in relatively large quantities compared to the remaining components of the composition.